Macrovascular diseases (CVD and stroke) steeply increase with age and account for >85% of chronic disease deaths in those >70 years of age (from Belsky et al. Proc. Natl. Acad. Sci. USA 2015). While cardiovascular disease (CVD) is the leading cause of death in the elderly, almost 60% of elderly patients with atherosclerotic CVD have either no or just one conventional CV risk factors (e.g. hypertension, hypercholesterolemia, etc.). As can be seen in Khot et al. (JAMA 2003), more than 60% of patients with CVD display either zero or one conventional risk factors. Similarly, retrospective analysis of CVD patients revealed that up to 50% of these patients were classified as low-risk when applying predictive scales based on traditional risk factors (Akosah et al. JACC 2003). Consistent with these findings, the recent PESA and AWHS studies have reported that subclinical atherosclerosis can be detected in more than 57% of asymptomatic adults categorized as “low CV risk” on the basis of conventional 10-year risk prediction algorithms (Fernández-Friera et al. Circulation 2015; Laclaustra et al. JACC 2016). Among others, these clinical studies suggest that there are as-yet-unidentified causal risk factors that drive cardiovascular disease in the human population.